In 1995, Searle and Molinski (J. Am. Chem. Soc. 1995, 117, 8126-8131; J. Am. Chem. Soc. 1996, 118, 9422-9423; Tetrahedron Lett. 1996, 37, 7879-7880) isolated (+)-Phorboxazole A (1) and B (2) from a methanolic extract of the sponge Phorbas sp. In vitro bioassay against the National Cancer Institute's (NCI) panel of 60 human tumor cell lines revealed extraordinary anti-proliferative activity against the entire panel; a mean GI50 value of 1.58×10−9 M for both (+)-Phorboxazole A and B.

While (1) and (2) remain promising anticancer medicinal agents, their architectural complexity warrants exploration of simplified synthetic analogs. Initial structure activity relationship (SAR) studies conducted by Uckun (WO 01/36048 A1)and Forsyth (Bioorg. Med. Chem. Lett. 2001, 11, 1181-1183) disclosed the discovery of two (+)-Phorboxazole A analogues which displayed anticancer activity in leukemia, breast cancer, and brain tumor cancer cell lines.
Several groups have been actively involved in devising synthetic routes to Phorboxazole A and/or Phorboxazole B. Forsyth, et al. (J. Am Chem. Soc. 1998, 120, 5597) have reported a linear synthetic sequence of 100 total steps to Phorboxazole A in 0.4% overall yield. Smith, et al., (J. Am. Chem. Soc. 2001, 123, 4834) have prepared Phorboxazole A in an overall yield of 3%. Pattenden, et al., (Angew. Chem. Int. Ed. 2003, 42, 1255) have provided Phorboxazole A in 0.18% overall yield. A 2.4% overall yield of Phorboxazole A was reported by Williams, et al. (Angew. Chem. Int. Ed. 2003, 42, 1258). Evans, et al (Angew. Chem. Int. Ed. 2000, 39, 2533, 2536) have developed a route to Phorboxazole B of 71 total steps in 12.6% overall yield.
There is therefore a need for improved synthetic methods which provide high yield and high selectivity, and at a relatively high rate of reaction, using better, more convenient and/or less expensive process methodology than many processes known heretofore for the preparation of Phorboxazole A, Phorboxazole B, their synthetic intermediates, and for compounds, analogs or derivatives having similar chemical and/or biological activity. The present invention is directed to these and other important ends.